P01AG071746

Estrogens, Cardiometabolic Health, and Female Cognitive Aging - Overall Summary

Loss of ovarian function at menopause is hypothesized to be a risk factor for Alzheimer's disease and related dementias. Research in preclinical models indicates that estrogens are neuroprotective and can positively impact the cognitive aging trajectory. However, clinical data have been equivocal as to the benefits of menopausal estrogen therapy to the brain and cognition. Variation in response to estrogen therapy in women suggests that pre-existing diseases such as hypertension and metabolic syndrome can modulate mechanisms of estrogen action. These alterations may consequently reduce or reverse protections estrogens provide against cognitive decline, Alzheimer's disease, and related dementias.

The program objective is to determine the impact of cardiometabolic status on the ability of exogenously administered estrogens to benefit the brain and cognition in an aging female rodent model. The overall hypothesis is that administration of estrogens in aging females will benefit the brain and cognition if initiated in healthy subjects, but will provide no benefits if initiated in the presence of cardiometabolic disease. Mechanisms by which these divergent effects occur are hypothesized to involve both alterations in mechanisms by which estrogens act directly on brain memory systems and mechanisms by which estrogens act on cardiometabolic systems, which in turn impact brain memory systems. Experiments under the four projects will test this hypothesis.

Project 1 will test the hypothesis that cardiometabolic disease, due to associated dysfunction of the ubiquitin/proteasome system, will disrupt the ability of estrogens to regulate levels of ERA in the hippocampus, regulation that is necessary for midlife estradiol treatment to exert lasting impacts on memory.

Project 2 will test the hypothesis that the presence of cardiometabolic disease impedes estrogen's beneficial cognitive effects by blunting neurovascular coupling via endothelial nitric oxide synthase uncoupling, thus impairing the local network activity and synaptic plasticity required to preserve functional cortical circuits and therefore for cognition.

Project 3 will test the hypothesis that cardiovascular disease alters the estrogen receptor profile, altering downstream molecular signaling pathways and attenuating its protective vascular effects and subsequent impact on cognition.

Project 4 will test the hypothesis that insulin resistance caused by a high-fat diet impairs downstream signaling pathways necessary for estradiol's beneficial influence on central regulation of glucose homeostasis, hippocampal long-term potentiation, and hippocampus-dependent cognitive function.

The Administrative Core will provide leadership to the program and ensure integration of all program components. The Cardiometabolic and Hormones and Behavior Cores will provide critical consistencies in models and procedures to ensure scientific rigor and reproducibility of results across projects.

Results will identify conditions under which estrogen treatment will (or will not) change the cognitive aging trajectory that could potentially reduce or delay age-related cognitive diseases, including Alzheimer's disease and vascular dementia.

The Administrators Of Tulane Educational Fund

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

New Orleans, Louisiana 701185665 United States

Single Zip Code

NIA Program Project Applications (P01 Clinical Trial Optional) (PAR-19-314)

Amendment Since initial award the total obligations have increased 308% from $2,822,728 to $11,521,268.